排序方式: 共有46条查询结果,搜索用时 15 毫秒
21.
Anne Lübbeke Sylvain Duc Guido Garavaglia Axel Finckh Pierre Hoffmeyer 《Obesity (Silver Spring, Md.)》2009,17(7):1414-1419
Obesity might be involved in the pathogenesis of osteoarthritis (OA) not only via increased mechanical loading, but also via an inflammatory component possibly causing increased pain and functional disability. The study aim was to examine the relationship between BMI and clinical symptoms as well as radiographic severity of OA in patients scheduled for primary total hip arthroplasty (THA). We conducted a cross‐sectional study of 855 patients scheduled for a first THA for primary OA at a single centre between November 2001 and December 2006. The primary outcome was clinical and radiographic severity of OA, which was evaluated in four BMI categories (18.5–24.9, 25–29.9, 30–34.9 and ≥35 kg/m2). We used the Harris Hip Score (HHS) and the Western Ontario McMaster Universities Osteoarthritis Index (WOMAC) to assess pain and function. The severity of radiographic hip joint damage was evaluated using the Kellgren–Lawrence classification. Multivariate analyses were performed to adjust for potential confounders. In patients scheduled for THA, increasing BMI was associated with significantly higher levels of pain and functional disability on both HHS (P for trend <0.001) and WOMAC (P for trend <0.001). However, the degree of radiographic joint damage remained similar across BMI categories. These findings emphasize the need to further investigate the potential pathogenic role of obesity and low‐grade inflammation in OA and underscore the importance of obesity prevention to avoid early prosthetic replacement of the hip. 相似文献
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Giacomo Monzio Compagnoni Giulio Kleiner Andreina Bordoni Francesco Fortunato Dario Ronchi Sabrina Salani Marianna Guida Corrado Corti Irene Pichler Christian Bergamini Romana Fato Maria Teresa Pellecchia Annamaria Vallelunga Francesca Del Sorbo Antonio Elia Chiara Reale Barbara Garavaglia Gabriele Mora Alessio Di Fonzo 《生物化学与生物物理学报:疾病的分子基础》2018,1864(12):3588-3597
Multiple System Atrophy is a severe neurodegenerative disorder which is characterized by a variable clinical presentation and a broad neuropathological spectrum. The pathogenic mechanisms are almost completely unknown. In the present study, we established a cellular model of MSA by using fibroblasts' primary cultures and performed several experiments to investigate the causative mechanisms of the disease, with a particular focus on mitochondrial functioning.Fibroblasts' analyses (7 MSA-P, 7 MSA-C and 6 healthy controls) displayed several anomalies in patients: an impairment of respiratory chain activity, in particular for succinate Coenzyme Q reductase (p?<?0.05), and a reduction of complex II steady-state level (p?<?0.01); a reduction of Coenzyme Q10 level (p?<?0.001) and an up-regulation of some CoQ10 biosynthesis enzymes, namely COQ5 and COQ7; an impairment of mitophagy, demonstrated by a decreased reduction of mitochondrial markers after mitochondrial inner membrane depolarization (p?<?0.05); a reduced basal autophagic activity, shown by a decreased level of LC3 II (p?<?0.05); an increased mitochondrial mass in MSA-C, demonstrated by higher TOMM20 levels (p?<?0.05) and suggested by a wide analysis of mitochondrial DNA content in blood of large cohorts of patients.The present study contributes to understand the causative mechanisms of Multiple System Atrophy. In particular, the observed impairment of respiratory chain activity, mitophagy and Coenzyme Q10 biosynthesis suggests that mitochondrial dysfunction plays a crucial role in the pathogenesis of the disease. Furthermore, these findings will hopefully contribute to identify novel therapeutic targets for this still incurable disorder. 相似文献
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Laura Pozzi Roberto Invernizzi Claudio Garavaglia & Rosario Samanin 《Journal of neurochemistry》1999,73(3):1051-1057
Fluoxetine at 10 and 25 mg/kg increased (167 and 205%, respectively) the extracellular dopamine concentration in the prefrontal cortex, whereas 25 (but not 10) mg/kg citalopram raised (216%) dialysate dopamine. No compound modified dialysate dopamine in the nucleus accumbens. The effect of 25 mg/kg of both compounds on cortical extracellular dopamine was not significantly affected by 300 mg/kg p-chlorophenylalanine (PCPA) (fluoxetine, saline, 235%; PCPA, 230%; citalopram, saline, 179%; PCPA, 181%). PCPA depleted tissue and dialysate serotonin by approximately 90 and 50%, respectively, and prevented the effect of fluoxetine and citalopram on dialysate serotonin (fluoxetine, saline, 246%; PCPA, 110%; citalopram, saline, 155%; PCPA, 96%). Citalopram significantly raised extracellular serotonin from 0.1 to 100 microM (251-520%), whereas only 10 and 100 microM increased dialysate dopamine (143-231%). Fluoxetine similarly increased extracellular serotonin (98-336%) and dopamine (117-318%). PCPA significantly reduced basal serotonin and the effects of 100 microM fluoxetine (saline, 272%; PCPA, 203%) and citalopram (saline, 345%; PCPA, 258%) on dialysate serotonin but did not modify their effect on dopamine (fluoxetine, saline, 220%; PCPA, 202%; citalopram, saline, 191%; PCPA, 211%). The results clearly show that the effects of fluoxetine and of high concentrations of citalopram on extracellular dopamine do not depend on their effects on serotonin. 相似文献
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Cremaschi D Porta C Bottà G Bazzini C Baroni MD Garavaglia M 《The Journal of membrane biology》2000,176(1):53-65
Cl− apically enters the epithelium of rabbit gallbladder by a Na+-Cl− symport, sensitive to hydrochlorothiazide (HCTZ). Since HCTZ also activates an apical SITS-sensitive Cl− conductance (G
Cl
), the symport inhibition might be merely due to a short circuit of the symport by G
Cl
rather than to a direct action of HCTZ on the symporter. To examine whether the symport is directly inhibited by HCTZ and
whether the symporter belongs to the family of thiazide-sensitive cotransporters (TSC), radiochemical measurements of the
apical Cl− uptake, electrophysiological determinations of intracellular Cl− and Na+ activities (a
i,Cl
and a
i,Na
) with selective theta microelectrodes and molecular biology methods were used. The 36Cl− uptake proved to be a measurement of the apical unidirectional Cl− influx (J
mc
) and of the symport only (without backflux components), with measuring times of 45 sec under all experiment conditions; its
inhibition by HCTZ was unaffected by G
Cl
activation or abolition. After HCTZ treatment the decrease in a
i,Cl
(measured as the initial rate or in 3 min) was larger than the decrease in a
i,Na
. The difference was reduced to one third in a group of epithelia in which the elicited G
Cl
was reduced to one third; moreover it was abolished in any case when G
Cl
was abolished with 10−4
m SITS. The SITS-insensitive rate of a
i,Cl
decrease was equal to that of the a
i,Na
decrease in any case. Thus the a
i,Cl
decrease displays a component dependent on G
Cl
activation and a second component dependent on symport inhibition. Using the RT-PCR technique a cDNA fragment was obtained
that was 99% identical to the corresponding region of the rabbit renal TSC isoform. The results indicate that in rabbit gallbladder
epithelium HCTZ displays a dual action, namely G
Cl
activation and Na+-Cl− symport inhibition. This Na+-Cl− symporter is the first TSC found to be functionally expressed in a nonrenal or nonrenal-like epithelium.
Received: 29 July 1999/Revised: 23 March 2000 相似文献
28.
Fürst J Schedlbauer A Gandini R Garavaglia ML Saino S Gschwentner M Sarg B Lindner H Jakab M Ritter M Bazzini C Botta G Meyer G Kontaxis G Tilly BC Konrat R Paulmichl M 《The Journal of biological chemistry》2005,280(35):31276-31282
ICln is a multifunctional protein involved in regulatory mechanisms as different as membrane ion transport and RNA splicing. The protein is water-soluble, and during regulatory volume decrease after cell swelling, it is able to migrate from the cytosol to the cell membrane. Purified, water-soluble ICln is able to insert into lipid bilayers to form ion channels. Here, we show that ICln159, a truncated ICln mutant, which is also able to form ion channels in lipid bilayers, belongs to the pleckstrin homology (PH) domain superfold family of proteins. The ICln PH domain shows unusual properties as it lacks the electrostatic surface polarization seen in classical PH domains. However, similar to many classical PH domain-containing proteins, ICln interacts with protein kinase C, and in addition, interacts with cAMP-dependent protein kinase and cGMP-dependent protein kinase type II but not cGMP-dependent protein kinase type Ibeta. A major phosphorylation site for all three kinases is Ser-45 within the ICln PH domain. Furthermore, ICln159 interacts with LSm4, a protein involved in splicing and mRNA degradation, suggesting that the ICln159 PH domain may serve as a protein-protein interaction platform. 相似文献
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Sabrina Dusi Lorella Valletta Tobias?B. Haack Yugo Tsuchiya Paola Venco Sebastiano Pasqualato Paola Goffrini Marco Tigano Nikita Demchenko Thomas Wieland Thomas Schwarzmayr Tim?M. Strom Federica Invernizzi Barbara Garavaglia Allison Gregory Lynn Sanford Jeffrey Hamada Concei??o Bettencourt Henry Houlden Luisa Chiapparini Giovanna Zorzi Manju?A. Kurian Nardo Nardocci Holger Prokisch Susan Hayflick Ivan Gout Valeria Tiranti 《American journal of human genetics》2014,94(1):11-22
Neurodegeneration with brain iron accumulation (NBIA) comprises a clinically and genetically heterogeneous group of disorders with progressive extrapyramidal signs and neurological deterioration, characterized by iron accumulation in the basal ganglia. Exome sequencing revealed the presence of recessive missense mutations in COASY, encoding coenzyme A (CoA) synthase in one NBIA-affected subject. A second unrelated individual carrying mutations in COASY was identified by Sanger sequence analysis. CoA synthase is a bifunctional enzyme catalyzing the final steps of CoA biosynthesis by coupling phosphopantetheine with ATP to form dephospho-CoA and its subsequent phosphorylation to generate CoA. We demonstrate alterations in RNA and protein expression levels of CoA synthase, as well as CoA amount, in fibroblasts derived from the two clinical cases and in yeast. This is the second inborn error of coenzyme A biosynthesis to be implicated in NBIA. 相似文献
30.
Garavaglia S Bruzzone S Cassani C Canella L Allegrone G Sturla L Mannino E Millo E De Flora A Rizzi M 《The Biochemical journal》2012,441(1):131-141
Haemophilus influenzae is a major pathogen of the respiratory tract in humans that has developed the capability to exploit host NAD(P) for its nicotinamide dinucleotide requirement. This strategy is organized around a periplasmic enzyme termed NadN (NAD nucleotidase), which plays a central role by degrading NAD into adenosine and NR (nicotinamide riboside), the latter being subsequently internalized by a specific permease. We performed a biochemical and structural investigation on H. influenzae NadN which determined that the enzyme is a Zn2+-dependent 5'-nucleotidase also endowed with NAD(P) pyrophosphatase activity. A 1.3?? resolution structural analysis revealed a remarkable conformational change that occurs during catalysis between the open and closed forms of the enzyme. NadN showed a broad substrate specificity, recognizing either mono- or di-nucleotide nicotinamides and different adenosine phosphates with a maximal activity on 5'-adenosine monophosphate. Sequence and structural analysis of H. influenzae NadN led us to discover that human CD73 is capable of processing both NAD and NMN, therefore disclosing a possible novel function of human CD73 in systemic NAD metabolism. Our data may prove to be useful for inhibitor design and disclosed unanticipated fascinating evolutionary relationships. 相似文献